Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D00031 (Glutathione)
5,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently demonstrated that endothelial cells are more susceptible than renal tubular epithelial cells to oxidant injury and that renal tubular epithelial cells with proximal tubular characteristics including porcine proximal tubular epithelial cells, opossum kidney proximal tubular epithelial cells, and normal human kidney cortical epithelial cells are more susceptible to oxidant injury than the distal nephron-derived Madin Darby canine kidney cell line. To determine the basis of this differential response, we evaluated several antioxidant defenses in the five cell lines. Glutathione levels were not significantly different among the five cell lines, but catalase and glutathione reductase levels were significantly (p less than 0.01) lower in endothelial cells compared to all renal tubular epithelial cells. Among renal tubular epithelial cells, Madin Darby canine kidney cells had significantly (p less than 0.05) higher glutathione peroxidase activity. To further evaluate the role of antioxidant defenses in limiting oxidant injury, we determined two responses to oxidant injury (ATP depletion and 51Cr release) when glutathione was depleted with buthionine sulfoxamine and when catalase was inhibited with aminotriazole. Oxidant-induced ATP depletion was accentuated when catalase was inhibited as well as when glutathione was depleted with buthionine sulfoxamine. In contrast, inhibition of catalase had little or no effect on 51Cr release, whereas glutathione depletion resulted in accentuated 51Cr release. We conclude that the increased susceptibility of endothelial cells to oxidant injury as compared with epithelial cells is associated with lower antioxidant defenses. Disruption of the glutathione redox cycle results in accentuated ATP depletion and lytic injury, whereas inhibition of catalase results in accentuated ATP depletion with little effect on lytic injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antioxidant defense mechanisms of endothelial cells and renal tubular epithelial cells in vitro: role of the glutathione redox cycle and catalase. 140 76

The UW solution for preservation of the liver, kidney, and pancreas contains a number of components, and the importance of each of these has not been fully resolved. In the studies reported here the importance of glutathione and adenosine is demonstrated in isolated cell models (rabbit renal tubules and rat liver hepatocytes) of hypothermic preservation and reperfusion and in dog renal transplantation. Glutathione in the UW solution is necessary for the preservation of the capability of the cell to regenerate ATP and maintain membrane integrity. Adenosine in the UW solution provides the preserved cell with substrates for the regeneration of ATP during the reperfusion period following cold storage. The omission of GHS from the UW solution results in poorer renal function in the 48 hr dog kidney preservation-transplant model. The role of other components of the UW solution is discussed including lactobionic acid; other impermeants; and the colloid, hydroxyethyl starch. It is concluded that the development of improved preservation solutions will require a more detailed understanding of the mechanism of injury due to cold storage and, once obtained, solutions more complex than the UW solution may be required for improved long-term storage of organs.
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PMID:Important components of the UW solution. 168 16

Freshly isolated adult rat heart myocytes contain total glutathione and reduced glutathione (GSH) at levels quite comparable to those in intact rat heart. Total glutathione can be depleted from 11 to 1 nmol/mg protein or less by treatment with cyclohex-2-ene-1-one without effect on either cellular ATP, rod-cell morphology or the integrity of the sarcolemma. Glutathione levels and redox state are not altered significantly when the Ca-tolerant, quiescent cells are subjected to a period of anoxia followed by reoxygenation. This oxygen paradox protocol results in irreversible hypercontracture of the contractile elements into an amorphous mass in the bulk of the cells, but little loss of sarcolemmal integrity. When the myocytes are subjected to an externally applied oxidant stress by the addition of either diamide or t-butylhydroperoxide, GSH is rapidly depleted with accumulation of oxidized glutathione (GSSG. On continued aerobic incubation both of these reagents promote a slower depletion of cellular ATP and a parallel hypercontracture. Cells treated with t-butylhydroperoxide, but not those with diamide, also generate increasing amounts of thiobarbituric acid reactive species as an indication of lipid peroxidation and show a parallel loss of sarcolemmal integrity. It is concluded that respiring myocytes and those subjected to the oxygen paradox do not produce oxygen radicals in sufficient amounts to displace the GSH/GSSG redox poise and depletion of myocyte glutathione per se is not detrimental to the short term survival of the cells. In addition, aerobic myocytes subjected to external oxidant stress can be damaged irreversibly by two pathways, a hypercontracture that correlates with depletion of ATP and a loss of sarcolemmal integrity that correlates with lipid peroxidation.
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PMID:Cellular glutathione and the response of adult rat heart myocytes to oxidant stress. 238 82

Glutathione, an essential cellular antioxidant required for mitochondrial function, is not synthesized by mitochondria but is imported from the cytosol. Rat liver mitochondria have a multicomponent system that underlies the remarkable ability of mitochondria to take up and retain glutathione. At external glutathione levels of less than 1 mM, glutathione is transported into the mitochondrial matrix by a high-affinity component (Km, approximately 60 microM; V max, approximately 0.5 nmol/min per mg of protein), which is saturated at levels of 1-2 mM and stimulated by ATP. Another component has lower affinity (Km, approximately 5.4 mM; Vmax, approximately 5.9 nmol/min per mg of protein) and is stimulated by ATP and ADP. Both components are inhibited by carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), glutamate, and ophthalmic acid. Increase of extramitochondrial glutathione promotes uptake and exchange; the intermembranous space seems to function as a recovery zone that promotes efficient recycling of matrix glutathione. The findings are in accord with in vivo data showing that (i) rapid exchange occurs between mitochondrial and cytosolic glutathione, (ii) lowering of cytosolic glutathione levels (produced by administration of buthionine sulfoximine) decreases export of glutathione from mitochondria to cytosol, and (iii) administration of glutathione esters increases glutathione levels in mitochondria more than those in the cytosol.
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PMID:High-affinity transport of glutathione is part of a multicomponent system essential for mitochondrial function. 240

Individual cells and cell pairs were isolated from frog lens epithelium. Individual cells were whole cell voltage clamped and the current-voltage relationship was determined. The cells had a mean resting voltage of -54.3 mV and a mean input resistance of 1.4 G omega. The current-voltage relationship was linear near the cell resting voltage, but showed decreased resistance with large depolarization or hyperpolarization. Junctional currents between pairs of cells were recorded using the dual whole cell voltage-clamp technique. The corrected junctional resistance was 15.5 M omega (64.5 nS). The junctional current-voltage relationship was linear. A combination of ATP and cAMP, in the electrodes, stabilized junctional resistance. Currents recorded when uncoupling was nearly complete, showed evidence of single connexion gating events. A single-channel conductance of about 100 pS was prominent. Dye spread between isolated cell pairs was demonstrated using Lucifer Yellow CH in a whole cell configuration. Photodamage to the cells due to the dye was apparent. Dye loaded cells, in the presence of exciting light, showed decreased resting voltages, decreased input resistances and morphological changes. Glutathione (20 mM) delayed this damage.
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PMID:Membrane and junctional properties of dissociated frog lens epithelial cells. 260 Sep 60

The biochemical mechanism of cytotoxicity, induced by the quinoid compound 2-methyl 1,4-naphthoquinone (menadione), was investigated in hepatocytes freshly isolated from fasted and fed rats. Hepatocytes from fasted rats were significantly more vulnerable to the toxicity of menadione than hepatocytes from fed rats. Menadione (150 microM) induced a 50% loss of viability of cells (LT50) from fasted rats after 55 min of incubation, whereas a LT50 of 80 min was observed after exposure of hepatocytes from fed rats to menadione. Glutathione and NADPH levels were rapidly depleted by menadione metabolism. This depletion was sustained during the incubation period. No significant differences were found in the time course and extent of the menadione-induced glutathione and NADPH depletion in hepatocytes of both nutritional states. Menadione also affected the energy status of the hepatocytes. The ATP content of cells from fasted rats decreased to 50% (AT50) within 18 min of exposure to menadione, whereas a 50% loss of ATP content of hepatocytes from fed rats was reached at 65 min. In contrast to depletion of glutathione and NADPH, the time course and extent of menadione-induced ATP depletion correlated well with the time of onset and rate of cell killing. Our results suggest that menadione metabolism may interfere with both mitochondrial and glycolytic ATP production. Depletion of ATP might be a critical step in menadione-induced cytotoxicity.
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PMID:Alterations in energy status by menadione metabolism in hepatocytes isolated from fasted and fed rats. 275 93

Extracellular reduction of ferricyanide was exhibited by isolated Cuscuta protoplasts. A larger decrease in NADH than NADPH levels of the ferricyanide-treated protoplasts pointed to the major involvement of the former as an electron donor. Glutathione levels were also found to be lowered in similarly treated tissue. The time-dependent variation in intracellular ATP levels in presence of ferricyanide supported the concept of plasma membrane ATPase activation during transplasma membrane electron transport in eukaryotes.
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PMID:Changes in intracellular redox and energy status during induced transplasma membrane electron transport in Cuscuta protoplasts. 297 17

Bordetella pertussis, the causative agent of whooping cough, releases pertussis toxin in an inactive form. The toxin consists of an A protomer containing one S1 peptide subunit and a B oligomer containing several other peptide subunits. The toxin binds to cells via the B oligomer, and the S1 subunit is activated and expresses ADP-ribosyltransferase and NAD glycohydrolase activities. Treatment of purified toxin with dithiothreitol (DTT) in vitro increases both activities. ATP and the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) synergistically reduce the A0.5 (activation constant) for DTT from greater than 100 mM to 200 microM. We studied the structure-activity relationships of activators of the toxin. In the presence of CHAPS (1%) and DTT (10 mM) the following compounds increased the NAD glycohydrolase activity of the toxin with the following A0.5's in microM and fraction of the ATP effect in parentheses: ATP, 0.2 (1.0); ADP, 6 (0.8); UTP, 15 (0.7); GTP, 35 (0.6); pyrophosphate, 45 (0.7); triphosphate, 60 (0.6); tetraphosphate, greater than or equal to 170 (greater than or equal to 0.4). Thus, the polyphosphate moiety is sufficient to stimulate the toxin, and the adenosine moiety confers upon ATP its extraordinary affinity for the toxin. Phospholipid and detergents could substitute for CHAPS in the activation of the toxin. Glutathione substituted for DTT with an A0.5 of 2 mM, a concentration within the range found in eucaryotic cells. Thus, membrane lipids and cellular concentrations of glutathione and ATP are sufficient to activate pertussis toxin without the need for a eucaryotic enzymatic process.
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PMID:Structure-activity analysis of the activation of pertussis toxin. 303 Mar 99

The plasma from rats injected with epinephrine (5 mg/kg) (epinephrine plasma) was found to be cytotoxic when incubated with isolated heart cells. This cytotoxicity was apparent 60 minutes after the start of the incubation due to the appearance at this time of membrane microblebs and microvilli as seen by scanning electron microscopy and the start of a fall in intracellular concentrations of ATP. The membrane blebs increased in size with time and the cells became contracted. Incubation of the cells for 90 minutes with epinephrine plasma, caused an increase in permeability of plasma membrane to 86Rb+. Incubation with alpha-tocopherol prevent this change. After 180 minutes incubation, these cells no longer retained carboxyfluorescein indicating that extensive membrane damage had occurred. It has been suggested that the presence of membrane blebs are evidence that lipid peroxidation is occurring in the cell membrane. Accordingly, glutathione, which is used by the cell against free radical attack and membrane lipid peroxidation, was measured. Glutathione levels started to fall after 60 minutes incubation, the time when the ultrastructural cell membrane changes started to occur. Pretreatment of cells with 100 microM 1,3-bis(2-chloroethyl)-1-nitrosourea which inhibits glutathione reductase, before the addition of plasma, increased the sensitivity of these cells to the epinephrine plasma, as measured by fall in intracellular ATP. Cells treated with control plasma did not show the changes described above. The nature of the cytotoxic factor in the plasma is still unknown, although the evidence presented suggests that a free radical may be involved.
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PMID:Epinephrine-induced cytotoxicity of rat plasma. Its effects on isolated cardiac myocytes. 319 96

Glutathione conjugation of aziridines was found in isolated rat hepatocytes in experiments using the optical isomers of (1- and d-) aziridinecarboxylic acid (AZC) and (1- and d-) 1-methyl-2-beta-naphthylaziridine (NAZ). 1-AZC much more effectively consumed glutathione than d-AZC, and the yield of the glutathione conjugate during 2 hr of incubation exceeded 200% of the cellular glutathione detected at the initiation of the incubation. Such a high yield of 1-AZC-GSH conjugate would occur only when conjugation efficiently proceeds without interference against the GSH resynthesis route in the liver cells. The cytotoxicity of 1-AZC was very weak and did not affect cell viability of the isolated hepatocytes even after the formation of AZC-GSH conjugate. Consequently, we supposed that GSH is not essential for supporting the viability of the isolated hepatocytes. For very slow GSH conjugate formation of d-AZC, we envisaged poor membrane transport of the d-isomer resembling to the selective incorporation of d- and 1-proline observed in some plant cells. Both isomers of NAZ were markedly cytotoxic and depressed the cell viability. The yield of the glutathione conjugate from NAZ did not exceed the cellular GSH level detected at the initial stage of incubation. The highly cytotoxic compound nitrosomethane, generated in the first biotransformation step of the metabolism of NAZ, can obstruct the resynthesis route of GSH by inhibiting the ATP generation process as discussed previously (Ref. 3). Decreasing the cellular GSH by treatment with 1-AZC enhanced the susceptibility of the isolated hepatocytes to NAZ toxicity. d-AZC did not affect the viability of cells treated with NAZ.
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PMID:Cellular glutathione conjugation of aziridines in isolated rat hepatocytes. 335 5


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